1. Field of the Invention
The invention relates to methods for the treatment of patients that are affected by a pulmonary disease. The methods typically involve the administration of aerosolized medicines. More specifically, the invention relates to compositions comprising disodium cromoglycate (DSCG) and therapeutic methods that include the pulmonary administration of such compositions.
2. Related Art
Asthma is a major cause of morbidity and mortality in the world and there is evidence that the prevalence has increased over the past 20 years, especially in children. Asthma is a chronic inflammatory disorder of the lung and often involves infiltration of the airway by inflammatory cells such as activated lymphocytes and eosinophils, denudation of the epithelium, deposition of collagen in the subbasement membrane area and mast cell degranulation. These inflammatory cells release chemical mediators resulting in altered airways physiology, swelling of the mucosa and submucosa, stripping of and damage to the epithelium, thickening of the basement membrane, excessive production of bronchial secretion and enlargement of the smooth muscle. It was observed in animal studies that the migration and activation of inflammatory cells is partly controlled by chemotactic agents, e.g. platelet activating factor (PAF) or leukotriene B4 (LTB4), and an increased expression of adhesion molecules with receptor-ligand systems to leukocytes on epithelium and on vascular endothelial cells supporting the migration of inflammatory cells into lung tissue.
In a biopsy-proven (airway smooth muscle) study without allergen challenge in 17 asthmatic patients, 13 patients with eosinophilic bronchitis and 11 normal subjects, a significant difference in submucosal eosinophil count, thickness of basement membrane and lamina reticularis in asthmatic patients and patients with eosinophilic bronchitis was observed compared to the control group, but no differences were observed in the asthma/bronchitis patients. Across the disease groups, the median number of tryptase-positive mast cells in the bundles of airway smooth muscle was significantly higher in asthma patients compared to bronchitis patients and normal subjects (p<0.001), thus raising an important inflammation process difference between eosinophilic bronchitis and asthma.
In a study in six mildly symptomatic asthmatics with biopsy evidence about 5 to about 6 hours after local allergen challenge, a significant increase in neutrophils, eosinophils, mast cells and CD3+ lymphocytes, but not for CD4+ or CD8+ lymphocyte counts. A significant increase of endothelial intercellular adhesion molecule type I and E-selectin was also observed. All subjects also developed a localized bronchoconstriction with a fall in forced expiratory volume in 1 second (FEV1) and decrease in metacholine provocation concentration necessary to reduce FEV1 by about 20%.
Several studies on lung tissue specimens from asthmatic patients have demonstrated that due to the larger surface area, more severe inflammatory and structural changes occur in the distal lung (airways less than about 2 mm in diameter) and lung parenchyma of asthmatic patients, which may have a significant effect on the pathogenesis and treatment of the disease. A significant inverse correlation (p=0.0014) could be found in 21 asthmatic patients between the percentage of predicted FEV1 and the CD4+ inflammatory cell density in alveolar tissue, which was not observed for proximal samples. It was observed in a clinical study using lung specimens from asthmatic and non-asthmatic subjects that based on the accumulation of T-cells and eosinophils, a similar but more severe inflammatory process is present in the peripheral airways compared with the central airways in patients with asthma. Another study revealed that cells expressing IL-5 mRNA were significantly elevated in airways below about 2 mm compared to larger airways. These findings suggest that an inhaler controller therapy of inflammatory processes in asthma may result in a sufficient deposition of the drug in the smaller airways that are less than about 2 mm in diameter.
While the asthma pathogenesis of adult and childhood asthma is the same, the adverse effects and treatment strategies in childhood asthma are different compared to consequences in adult asthma patients. Early diagnosis and consecutive therapy are crucial for the short and long-term prognosis of this disease. Airway inflammation is treated according to the early intervention strategy with inhaled corticosteroids. In order to avoid side effects, such as growth retardation, the lowest therapeutically effective dose should be administered to children. Current nebulizers and pressurized metered dose inhalers (pMDIs) with spacers have been primarily developed for adults and have been adapted but not designed for use in young children. Lung deposition in adults from currently available nebulizers and pMDI/spacers ranges from about 8% to about 45% of the nominal dose, whereas studies in young children have shown lung deposition of only about 0.67% to about 5.4% of the nominal dose. This finding may suggest that aerosol droplets delivered by these devices are too large for the nose throat passage in young children.
Among many parameters, three major physiological differences affect pulmonary drug administration and should be considered for effective treatment for children 12 months to 8 years of age: (1) airway diameters of young children are significantly smaller than those of adults and older children; (2) younger children primarily inhale through the nose. Thus, a tight fitting facemask is needed to deliver the drug to the lungs. Consequently, lung deposition is significantly lower when inhaling through the nose versus inhalation via the oral route; and (3) the respiratory breathing patterns of young children are different from older children and adults with respect to the tidal volume (TV)—for infants is in the range of about 50 ml to about 100 ml, and respiratory rates—for infants is about 30 breaths per minute. The inspiratory flow (infants: in the range of about 3.5/min to about 15/min) may be too low to keep up with the driving flow of many nebulizer compressor configurations, so most of the nebulizer output is wasted.
Due to its excellent safety profile, inhaled disodium cromoglycate (DSCG) is used mainly as a controller medication for asthma in children, but its use now in childhood asthma management is in steep decline. One of the earliest studies investigating the mechanism of action of DSCG showed that the drug inhibited the influx of calcium ions and phosphorylated a 78 kDa protein in rat mast cells. These findings were associated with an inhibition of histamine release following antigen challenge, thus proposing a mast cell stabilizing effect. An identical phosphorylation trough cyclic guanosine monophosphate (cGMP) caused by a reaction of DSCG was investigated. This study indicated that the 78 kDa protein may be a substrate for cGMP-related phosphorylation. In addition, a cross-tachyphylaxis between the inhibitory effects of DSCG and cGMP on histamine release from rat peritoneal mast cells has been found.
Yet another study described the existence of a small conductance chloride channel in rat peritoneal mast cells which may be activated by cGMP and high intracellular calcium leading to an influx of chloride ions, hyperpolarization of the mast cell membrane, calcium influx and finally causing mast cell degranulation associated with inflammatory mediator release. DSCG has been shown to block intermediate conductance chloride channels which were activated following immunological stimulation of mucosa-like mast cells and colonic carcinoma epithelial cells. Thus, by preventing chloride channel activation trough DSCG, inflammatory cells may maintain a normal resting physiological state and may prevent release of inflammatory mediators. The maintenance of the physiological state may also explain the excellent safety profile of DSCG.
DSCG is currently available in the form of compositions for oral, nasal, ophthalmic, and pulmonary administration. Within the group of products for pulmonary inhalation, the known formulations are designed for administration as pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and nebulized aerosols.